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Conclusions and Perspectives
The results obtained so far on the cellular mechanism by which fluoride may influence the growth and differentiation of osteoblastic cell lines strongly suggest alteration of one or several G protein-dependent tyrosine phosphorylation process(es), activation of the ERK, and possibly other signaling pathways. There is a controversy of whether enhancement of tyrosine phosphorylation induced by fluoride results from inhibition of tyrosine phosphatase(s) or activation of tyrosine kinase(s), and evidence for either mechanism has been presented in this mini-review. For both working hypotheses, further investigation is required to determine the molecular target(s) responsible for inducing the alteration in tyrosine phosphorylation and enhancement of cell proliferation.
Despite the fact that the clinical application of fluoride in the treatment of osteoporosis remains controversial, the elucidation of its action mechanism at the molecular level will certainly provide useful information for the development of new pharmacological agents able to enhance osteoblastic proliferation and ultimately correct the deficit of bone mass and strength in osteoporosis.
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Heterotrimeric G proteins as fluoride targets in bone (review).
Fluoride is an acknowledged bone anabolic agent. Nevertheless, a narrow therapeutic window and the adverse effects at higher therapeutic doses prevent broad clinical application of fluoride for treatment of diseases of bone loss, such as osteoporosis. The cellular and molecular mechanisms of fluoride action are poorly understood. Recent advances in
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Sodium fluoride modulates caprine osteoblast proliferation and differentiation
The cellular and molecular pathways of fluoride toxicity in osteoblasts are not very well understood. Therefore, the objective of the present study was to evaluate the effects of sodium fluoride (NaF) on caprine osteoblasts cultured in vitro. Caprine osteoblasts at 2.0 x 10(-4) cells/ml were incubated in vitro with NaF
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De novo expression of the class-A macrophage scavenger receptor conferring resistance to apoptosis in differentiated human THP-1 monocytic cells.
The class-A macrophage scavenger receptor (MSR) is a trimeric multifunctional protein expressed selectively in differentiated monomyeloid phagocytes which mediates uptake of chemically modified lipoproteins and bacterial products. This study investigated whether MSR plays a role in the regulation of apoptosis, a model of genetically programmed cell death. De novo expression
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Distribution of Fluoride in Plasma, Brain, and Bones and Associated Oxidative Damage After Induced Chronic Fluorosis in Wistar Rats.
The study was aimed to determine fluoride levels in plasma, brain, and bones of Wistar rats following chronic administration of fluoride at different dose levels and the consequent oxidative damage inflicted in these tissues. Brain histomorphology and bone radiographs were also evaluated to assess the extent of damage in these
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Role of fluoride induced epigenetic alterations in the development of skeletal fluorosis.
Highlights WGBS data depict altered methylation of genes regulating bone development pathways. Fluoride causes diminished expression of BMP1, METAP2, MMP11 and BACH1 genes. These genes play a critical role in catabolic process of skeletal development. DNA hypermethylation of these critical genes thus promote skeletal fluorosis. Fluoride is an essential trace element
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"Pre-Skeletal" Fluorosis
As demonstrated by the studies below, skeletal fluorosis may produce adverse symptoms, including arthritic pains, clinical osteoarthritis, gastrointestinal disturbances, and bone fragility, before the classic bone change of fluorosis (i.e., osteosclerosis in the spine and pelvis) is detectable by x-ray. Relying on x-rays, therefore, to diagnosis skeletal fluorosis will invariably fail to protect those individuals who are suffering from the pre-skeletal phase of the disease. Moreover, some individuals with clinical skeletal fluorosis will not develop an increase in bone density, let alone osteosclerosis, of the spine. Thus, relying on unusual increases in spinal bone density will under-detect the rate of skeletal fluoride poisoning in a population.
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Skeletal Fluorosis: The Misdiagnosis Problem
It is a virtual certainty that there are individuals in the general population unknowingly suffering from some form of skeletal fluorosis as a result of a doctor's failure to consider fluoride as a cause of their symptoms. Proof that this is the case can be found in the following case reports of skeletal fluorosis written by doctors in the U.S. and other western countries. As can be seen, a consistent feature of these reports is that fluorosis patients--even those with crippling skeletal fluorosis--are misdiagnosed for years by multiple teams of doctors who routinely fail to consider fluoride as a possible cause of their disease.
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Fluoride & Osteoarthritis
While the osteoarthritic effects that occurred from fluoride exposure were once considered to be limited to those with skeletal fluorosis, recent research shows that fluoride can cause osteoarthritis in the absence of traditionally defined fluorosis. Conventional methods used for detecting skeletal fluorosis, therefore, will fail to detect the full range of people suffering from fluoride-induced osteoarthritis.
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